The preclinical project, Adaptive Therapeutics Development in Rat Models, will determine the efficacy of new therapies in rodent models of nicotine self-administration (SA). These models will be used to screen promising new compounds and to elucidate the neurobehavioral mechanisms underlying the effectiveness of the treatments, so that further improvements can be made. To follow-up the demonstration that pre-quit date nicotine therapy significantly increases successful smoking cessation, we will test selective ligands of nicotinic receptor subtypes beginning with a4B2 and a7 receptors for reducing nicotine SA. Our prior research has shown the importance of these receptors for the initiation and persistence of nicotine SA, respectively. Nicotine has cascading effects of stimulating the release of a variety of transmitters and these interacting systems are important for the variety of neurobehavioral substrates for nicotine reinforcement. One promising and relatively understudied transmitter system that interacts with nicotinic systems is the serotonergic system. Serotonergic 5HT2A+C antagonism has been shown in our previous studies to decrease nicotine SA in acute and chronic studies. We will determine which subtype, 5HT2A or 5HT2C is responsible for the effect so that we can avoid undue side effects of combined 5HT2A+C treatment. Neuroactive steroids such as pregnenolone sulfate and DHEA have shown promise for smoking cessation. We will determine the mechanistic bases for reducing nicotine SA via actions on GABA and glutamate receptors. These treatments will be assessed in models of IV nicotine SA driven by consummatory motor habit in comparison to the classic model of lever press response. These models of different drives for nicotine SA will be used to determine how different treatments affect the various motivating factors for nicotine SA. Anatomic localization studies with local brain region infusions will be used to determine the circuitry underlying the efficacy of the treatments found to be effective on a systemic level. The preclinical studies will further the Center's primary goal of developing more effective treatments to aid smoking cessation by: a) testing novel pharmacologic agents to reduce nicotine SA; b) determining neurobehavioral mechanisms for their effect; and c) mapping the neuroanatomic substrates for the effect to inform the optimal development of adaptive treatments that will help more people successfully quit smoking.